This Grand Opportunity (RC2) grant is written in response to NHLBI call for proposals on Large-scale DNA Sequencing and Molecular Profiling of Well-phenotyped NHLBI Cohorts and the addendum portion describing Molecular Profiling. The identification of molecular predictors of cardiovascular risk is of great interest, not only because of their potential to significant improve our ability to make more refined and accurate assessment of disease burden and risk in the clinical environment, but also because of the power they provide to understand the biology of coronary artery disease and event risk in this unpredictable disease. In order to make advancements in risk assessment and new therapeutic approaches, it is imperative that we understand the genetic architecture of molecular markers in prospective study cohorts where the study subjects have been exquisitely characterized and phenotyped and on which follow-up is complete and detailed. Cohort. The project will use the Duke CATHGEN biorepository, which is a prospective cohort of individuals enrolled upon first encounter with the Duke Cardiac Catheterization Laboratory between January 2001 and present. All individuals obtain follow-up health status surveys at six months and then yearly following their first encounter. Also, yearly death is assessed using publically available resources, such as the National Death Index. The project will focus on subsequent events (primarily myocardial infarction and death). Medication data are available on all members of the study cohort. Molecular Profiling. We have already obtained focused metabolic profiling on 2000 matched cases and controls (1000 of each) from this cohort and observed significant metabolic predictors of subsequent events irrespective of disease status. Also, we recently have published data from this cohort showing significant predictive power of peripheral gene expression biomarkers. Finally, a detailed predictor model is being constructed on this cohort, where the input is readily available and well know clinical predictors of cardiovascular risk. Aims. In this study, we propose to: 1) Perform peripheral gene expression profiling on the same 2000 subject cohort in which the metabolic profiling has been performed;2) Perform a GWAs in this same cohort. Once significant genetic, and peripheral gene expression predictors are available, we will: 3) Define the predictive power of the molecular predictors alone and in combination with the clinical model;4) Define the molecular pathways defined by the genetic variants and the proportion of risk that is due to genetic contributors. PUBLIC HEALTH RELEVANCE: Personalized medicine, a goal of the current health goals of the country, requires methods to identify and quantify individual risk. In order to make advancements in risk assessment and develop new therapeutic approaches, it is imperative that one understand the genetic architecture of molecular markers in prospective study cohorts where the study subjects have been exquisitely characterized and phenotyped and on which follow-up is complete and detailed. We will combine knowledge of peripheral small molecular metabolic markers of cardiovascular risk, peripheral gene expression profiles and a genome wide SNP screen to develop comprehensive molecular profiles of cardiovascular risk.